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Diagnosis and Management of Eosinophilic Esophagitis: Updated ACG Clinical Guideline Summary

14 Jan, 2025 | 13:46h | UTC

Introduction: This summary highlights the updated American College of Gastroenterology (ACG) Clinical Guideline on eosinophilic esophagitis (EoE), a chronic, immune-mediated disease of the esophagus characterized by esophageal eosinophilia and clinical symptoms of esophageal dysfunction. Over the last decade, the incidence and prevalence of EoE have increased significantly. This guideline incorporates new diagnostic strategies, therapeutic advances, and monitoring practices, aiming to improve patient outcomes and minimize disease complications such as strictures, food impactions, and impaired quality of life. The document underscores the importance of assessing both the inflammatory and fibrostenotic components of EoE through endoscopy, histopathology, and symptom evaluation.

Key Recommendations:

Diagnosis:
- Diagnose EoE when patients present with symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (eos/hpf) on esophageal biopsies, after exclusion of other causes of esophageal eosinophilia.
- Use a systematic scoring tool such as the EoE Endoscopic Reference Score (EREFS) to assess edema, rings, exudates, furrows, and strictures at every endoscopy.
- Obtain at least six esophageal biopsies from two or more levels (e.g., distal and proximal) to minimize diagnostic miss rates; quantify peak eosinophil counts in each specimen.
Pharmacologic Therapy:
1. Proton Pump Inhibitors (PPIs):
  - Consider high-dose PPIs (e.g., twice daily) as a first-line treatment option. Although originally used for acid suppression, PPIs also reduce eotaxin-3 expression and improve esophageal barrier function in EoE.
  - Maintain therapy long term in patients who respond, as discontinuation frequently leads to disease recurrence.
2. Topical Corticosteroids (Swallowed Steroids):
  - Budesonide or fluticasone can be delivered via specially formulated suspensions/tablets or by swallowing inhaler medication.
  - Expect histologic remission rates of around 60%–70%.
  - Oral/esophageal candidiasis is the most common adverse event. Routine adrenal suppression testing is generally not necessary for short-term use.
3. Dietary Elimination:
  - Empiric elimination diets (e.g., 2-food or 6-food elimination) help identify specific food triggers. Histologic remission rates can exceed 70%, particularly with the 6-food approach.
  - Less-restrictive diets (e.g., milk-only elimination) may be tried first (the “step-up” approach).
  - Do not rely on currently available skin prick or Ig-based tests to guide elimination diets, as these have poor predictive value for EoE triggers.
4. Biologic Therapy:
  - Dupilumab (anti–IL-4 receptor alpha) is recommended in adolescents and adults (≥12 years, ≥40 kg) and is now approved for children as young as 1 year (≥15 kg) with moderate to severe, PPI-refractory EoE. Expect significant histologic, endoscopic, and symptom improvements in most patients, along with an overall favorable safety profile.
  - Other biologics (e.g., cendakimab, benralizumab, mepolizumab) remain under investigation; current data are insufficient for routine clinical use.
5. Esophageal Dilation:
  - Perform endoscopic dilation to treat symptomatic strictures or narrow-caliber esophagi. Dilation reduces dysphagia promptly but does not alter the underlying inflammation.
  - Combine dilation with anti-inflammatory therapy to address the disease’s inflammatory component and help prevent recurrent stricture formation.
Maintenance and Monitoring:
- Because EoE is chronic, continue effective therapy over the long term. Abrupt cessation of treatment often leads to relapses in symptoms and inflammation.
- Evaluate treatment response by assessing symptoms, endoscopic findings (e.g., EREFS), and histopathology (peak eosinophil counts).
- A target of <15 eos/hpf and near-normal endoscopic appearance (EREFS ≤2) is commonly used to define remission, although some patients aim for histologic normalization.
- In children, ensure regular assessment of growth, development, and feeding behaviors. Referral to a nutritionist or feeding therapist is recommended if feeding difficulties or failure to thrive are present.

Conclusion: These updated ACG guidelines underscore the importance of a comprehensive, individualized approach to EoE that encompasses diagnosis, treatment of the inflammatory state, dilation of fibrotic strictures, and ongoing monitoring to maintain long-term remission. The introduction of biologics (particularly dupilumab) expands treatment options for patients nonresponsive to PPIs or topical steroids. Clinicians should adopt a structured assessment strategy—integrating clinical history, endoscopic scoring, and histological evaluation—to guide therapy selection, document treatment response, and prevent complications. With improved understanding of disease pathogenesis and evolving therapeutic tools, outcomes for patients with EoE are expected to continue to improve.

Reference: Dellon ES, Muir AB, Katzka DA, Shah SC, Sauer BG, Aceves SS, Furuta GT, Gonsalves N, Hirano I. ACG Clinical Guideline: Diagnosis and Management of Eosinophilic Esophagitis. The American Journal of Gastroenterology. 2025;120(1):31–59. DOI: https://doi.org/10.14309/ajg.0000000000003194

Phase 2 RCT: CRISPR-Based Therapy Reduces Attacks in Hereditary Angioedema

2 Jan, 2025 | 10:00h | UTC

Background: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by unpredictable attacks of angioedema involving cutaneous tissues, the gastrointestinal tract, and, potentially, the larynx, posing a risk of asphyxiation. Current prophylactic treatments require frequent administration, often leading to suboptimal adherence and ongoing disease burden. NTLA-2002 is an in vivo CRISPR-Cas9–based therapy designed to permanently inactivate the KLKB1 gene in hepatocytes, thereby reducing plasma kallikrein levels and, hypothetically, lowering attack frequency in patients with HAE.

Objective: To evaluate whether a single intravenous infusion of NTLA-2002 (25 mg or 50 mg) would safely and effectively decrease HAE attack rates and reduce plasma kallikrein protein levels over a 16-week primary observation period, as compared with placebo.

Methods: This phase 2, randomized, double-blind, placebo-controlled trial included 27 adults with confirmed type 1 or type 2 HAE. Participants were assigned in a 2:2:1 ratio to receive a one-time dose of 25 mg or 50 mg of NTLA-2002 or placebo. The primary endpoint was the investigator-confirmed number of angioedema attacks per month from Week 1 through Week 16. Secondary endpoints included the number of moderate-to-severe attacks, use of on-demand therapy, adverse events, and changes in total plasma kallikrein protein levels (analyzed by immunoassays). Exploratory measures encompassed patient-reported outcomes using the Angioedema Quality of Life (AE-QoL) questionnaire.

Results: During the 16-week period, the mean monthly attack rate decreased by 75% in the 25 mg group and 77% in the 50 mg group relative to placebo (estimated rates of 0.70 vs. 0.65 vs. 2.82 attacks per month, respectively). Notably, 4 of 10 patients (40%) in the 25 mg group and 8 of 11 (73%) in the 50 mg group reported no attacks or further prophylaxis use after dosing. Placebo recipients showed only a 16% reduction from baseline. Adverse events were predominantly mild to moderate; headache, fatigue, and nasopharyngitis were most common. Infusion-related reactions occurred in a few patients but resolved without sequelae. A single transient grade 2 elevation in alanine aminotransferase was recorded in one participant given 25 mg of NTLA-2002. By Week 16, total plasma kallikrein levels decreased by 55% in the 25 mg group and 86% in the 50 mg group, with no meaningful changes in placebo.

Conclusions: A single intravenous infusion of NTLA-2002 significantly lowered attack frequency and reduced total plasma kallikrein levels in HAE. Most patients treated at 50 mg experienced no attacks, suggesting that long-term prophylaxis might be unnecessary for many. Longer observation supports durability, yet cost and potential long-term effects of gene editing warrant cautious interpretation.

Implications for Practice: If confirmed by larger phase 3 trials, this gene-editing approach could alter the management of HAE, reducing or eliminating the need for continuous prophylaxis. However, clinicians must weigh the high upfront cost, possible unpredictable immune responses, and the novelty of CRISPR-based therapies before integrating them into standard care.

Study Strengths and Limitations: Strengths include a placebo-controlled design, meaningful improvement in patient-reported outcomes, and robust plasma kallikrein protein reduction. Limitations are the small sample size, short primary observation period, and uncertain long-term safety in diverse populations.

Future Research: Ongoing phase 3 studies with larger cohorts and extended follow-up are essential to confirm safety, long-term efficacy, and cost-effectiveness.

Reference: Cohn DM, Gurugama P, Magerl M, et al. CRISPR-Based Therapy for Hereditary Angioedema. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2405734

Editorial: Musunuru K. A Milestone for Gene-Editing Therapies. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMe2412176

Review: Diagnosis and Management of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

18 Dec, 2024 | 11:08h | UTC

Introduction: DRESS is a severe T-cell–mediated hypersensitivity reaction triggered by prolonged exposure to certain medications, characterized by extensive rash, fever, hematologic abnormalities (notably eosinophilia or atypical lymphocytosis), lymphadenopathy, and involvement of internal organs such as the liver, kidneys, and lungs. Common culprits include aromatic anticonvulsants, allopurinol, and specific antibiotics. Although relatively rare, DRESS accounts for a substantial proportion of severe cutaneous adverse drug reactions (SCARs) in hospitalized patients and can be life-threatening, with mortality rates around 5%. Its pathogenesis involves complex immune dysregulation, including Th2 predominance, possible viral reactivation (e.g., HHV-6), and genetic predispositions related to certain HLA alleles. Diagnosis typically relies on clinical criteria, such as the validated RegiSCAR scoring system, and on excluding other SCARs like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).

Key Recommendations:

Identify and Discontinue the Culprit Drug: Prompt removal of the offending medication is the cornerstone of therapy.
Supportive Care and Monitoring: Hospitalization, often in an intensive care setting, may be required for organ function support and close monitoring of disease progression. Regular assessment of liver enzymes, renal function, blood counts, and cardiac and pulmonary status is critical.
Systemic Glucocorticoids: High-dose corticosteroids (e.g., prednisone 0.5–1 mg/kg/day) are first-line therapy. A gradual taper over 6–12 weeks is recommended to minimize relapse.
Steroid-Sparing and Targeted Therapies: In refractory cases or when steroids are contraindicated, consider other immunosuppressants (e.g., cyclosporine, mycophenolate mofetil) or targeted biologic agents (e.g., anti–IL-5 therapies) to control persistent eosinophilia and organ involvement.
Diagnostic Testing and Specialist Involvement: Although no single test confirms DRESS, dermatology or allergy/immunology consultation may help identify culprit drugs and safer therapeutic alternatives. Patch testing, delayed intradermal testing, and HLA genotyping can sometimes clarify drug causality.
Long-Term Follow-Up: Patients require prolonged observation due to risks of relapse, potential autoimmune sequelae (e.g., thyroiditis, type 1 diabetes), and psychological distress. Ongoing multidisciplinary care and support are essential.

Conclusion: Early recognition of DRESS, prompt discontinuation of the offending drug, and initiation of systemic corticosteroids are key steps in management. Emerging therapies offer additional treatment options for severe or refractory cases. Long-term follow-up is vital to address relapses, organ damage, and autoimmune complications. A coordinated, multidisciplinary approach improves clinical outcomes and quality of life for affected patients.

Reference: Kroshinsky D, Cardones ARG, Blumenthal KG. Drug Reaction with Eosinophilia and Systemic Symptoms. New England Journal of Medicine. 2024;391:2242-2254. DOI: https://doi.org/10.1056/NEJMra2204547

Review: Chronic Hand Eczema

29 Nov, 2024 | 12:28h | UTC

Introduction: Hand eczema is a highly prevalent inflammatory skin condition and one of the most common work-related disorders, with a lifetime prevalence of approximately 15%. In up to two-thirds of affected individuals, the disease becomes chronic—persisting for more than three months or recurring multiple times within a year—leading to substantial personal and occupational disability. This review by Weidinger and Novak synthesizes current knowledge on the epidemiology, risk factors, clinical features, diagnosis, mechanisms, and management of chronic hand eczema, highlighting the need for further research to enhance prevention and treatment strategies.

Key Recommendations:

Risk Factor Identification: Recognize major risk factors, including current or past atopic dermatitis, dry skin, and occupational exposure to irritants and allergens. Occupational history is crucial, as hand eczema is prevalent in high-risk professions such as health care, hairdressing, and cleaning.
Diagnosis and Assessment: Diagnose chronic hand eczema based on history and clinical features, considering differential diagnoses like psoriasis and tinea manus. Patch testing is recommended to identify contact allergens, especially in cases unresponsive to initial therapy.
Patient Education and Prevention: Implement structured education on skin care, avoidance of trigger factors, and use of protective measures. Emphasize primary to tertiary prevention strategies, including workplace interventions and rehabilitation programs.
Topical Therapies: Initiate treatment with topical glucocorticosteroids for anti-inflammatory effect. Use calcineurin inhibitors as second-line therapy, particularly for patients refractory to steroids or requiring long-term treatment. The topical pan-Janus kinase inhibitor delgocitinib is approved for moderate to severe chronic hand eczema unresponsive to corticosteroids.
Phototherapy: Consider short-term phototherapy (4–8 weeks) with options like PUVA or narrow-band UVB for patients inadequately controlled with topical treatments.
Systemic Therapies: For severe cases unresponsive to topical treatments, systemic retinoids such as alitretinoin are first-line therapy. Off-label use of immunosuppressants like ciclosporine, methotrexate, and azathioprine may be considered. Systemic immunomodulatory therapies approved for atopic dermatitis, including dupilumab and Janus kinase inhibitors, show promise, especially in atopic hand eczema.
Adjunctive Measures: Encourage the use of emollients for skin barrier repair and recommend avoidance of harmful exposures. Patient self-management is crucial, including appropriate hand hygiene and use of protective gloves.

Conclusion: By adopting these evidence-based management strategies, clinicians can improve patient care by reducing symptoms, preventing disease progression, and enhancing quality of life for individuals with chronic hand eczema. Early identification of risk factors, comprehensive patient education, and individualized treatment plans are essential to mitigate the substantial personal and socioeconomic burden of this condition.

Reference: Weidinger S, Novak N. Hand eczema. The Lancet. 2024. DOI: http://doi.org/10.1016/S0140-6736(24)01810-5

Cohort Study: Metformin Linked to Fewer Asthma Attacks in Patients with Asthma and Type 2 Diabetes

24 Nov, 2024 | 20:36h | UTC

Background: Patients with asthma frequently have comorbid obesity and type 2 diabetes (T2D), conditions associated with an increased risk of asthma attacks. Experimental studies suggest that metformin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) can reduce airway inflammation and hyperresponsiveness. However, epidemiological evidence supporting these effects is limited.

Objective: To evaluate the association between metformin use, with or without add-on antidiabetic medications, and the risk of asthma attacks in patients with asthma and T2D.

Methods: This study utilized data from the UK Clinical Practice Research Datalink Aurum from 2004 to 2020, employing two analytical approaches: a self-controlled case series (SCCS) of 4,278 new metformin users with asthma who experienced asthma attacks, and a population-based cohort study using inverse probability of treatment weighting (IPTW) including 8,424 patients. The primary exposure was initiation of metformin; secondary exposures included add-on antidiabetic medications. The primary outcome was the first asthma exacerbation—defined as a short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death—during 12 months of follow-up.

Results: Metformin use was associated with a significant reduction in asthma attacks in both analyses. In the SCCS, metformin initiation was linked to a 32% reduction in risk (incidence rate ratio [IRR], 0.68; 95% CI, 0.62-0.75). In the IPTW cohort, metformin use was associated with a 24% reduction (hazard ratio [HR], 0.76; 95% CI, 0.67-0.85). Addition of GLP-1RAs led to a further reduction in asthma attacks (IRR, 0.60; 95% CI, 0.49-0.73). Associations were consistent regardless of glycemic control, body mass index, asthma severity, or blood eosinophil counts.

Conclusions: The findings suggest that metformin use is associated with a lower rate of asthma attacks among patients with asthma and T2D, with additional benefits when GLP-1RAs are added. These effects appear independent of glycemic control or weight loss and occur across different asthma phenotypes.

Implications for Practice: These results indicate potential for repurposing metformin as an adjunct therapy to reduce asthma attacks in patients with asthma and T2D. However, as observational studies cannot establish causality, clinicians should interpret these findings cautiously. The higher cost and side-effect profile of GLP-1RAs warrant careful consideration before widespread adoption.

Study Strengths and Limitations: Strengths include a large, nationally representative sample and the use of two distinct analytical methods to enhance robustness. Limitations involve the observational design, which cannot confirm causality, and potential residual confounding factors such as medication adherence and dosage. Additionally, possible misclassification of asthma diagnosis and lack of data on changes in weight may affect the findings.

Future Research: Randomized controlled trials are necessary to confirm these findings and elucidate the mechanisms by which metformin and GLP-1RAs may reduce asthma attacks. Further studies should explore the benefits of early pharmacological intervention with antidiabetic medications in patients with asthma and metabolic dysfunction.

Reference: Lee B, et al. Antidiabetic Medication and Asthma Attacks. JAMA Internal Medicine. 2024. DOI: http://doi.org/10.1001/jamainternmed.2024.5982

RCT: Atrasentan Reduces Proteinuria in Patients with IgA Nephropathy

3 Nov, 2024 | 18:29h | UTC

Background: IgA nephropathy is the most common primary glomerular disease worldwide, leading to a substantial risk of kidney failure. Despite treatment with renin–angiotensin system (RAS) inhibitors, many patients experience persistent proteinuria and progressive kidney function decline. Endothelin-1, acting via the endothelin type A receptor, contributes to the disease’s pathophysiology. Atrasentan, a selective endothelin type A receptor antagonist, has shown potential in reducing proteinuria in prior studies.

Objective: To evaluate the efficacy and safety of atrasentan in reducing proteinuria among patients with IgA nephropathy.

Methods: In this phase 3, multinational, double-blind, randomized controlled trial, adults with biopsy-proven IgA nephropathy, urinary protein excretion of at least 1 g/day, and an estimated glomerular filtration rate (eGFR) of at least 30 ml/min/1.73 m² were enrolled. Patients on maximum tolerated doses of ACE inhibitors or ARBs were randomized 1:1 to receive atrasentan (0.75 mg/day) or placebo for 132 weeks. The primary outcome was the change in the 24-hour urinary protein-to-creatinine ratio from baseline to week 36, assessed in a prespecified interim analysis of the first 270 patients.

Results: Among these patients (135 per group), the geometric mean percentage reduction in the urinary protein-to-creatinine ratio at week 36 was significantly greater with atrasentan (−38.1%) compared to placebo (−3.1%), yielding a between-group difference of −36.1 percentage points (95% CI, −44.6 to −26.4; P<0.001). Adverse events were similar between groups. Fluid retention was reported in 11.2% of the atrasentan group and 8.2% of the placebo group but did not lead to discontinuation. No cases of cardiac failure or severe edema occurred.

Conclusions: Atrasentan significantly reduced proteinuria compared to placebo in patients with IgA nephropathy without significant safety concerns.

Implications for Practice: Atrasentan may serve as an effective additional therapy for patients with IgA nephropathy who remain at high risk of progression despite standard care, potentially influencing clinical decision-making toward more aggressive proteinuria reduction strategies.

Study Strengths and Limitations: Strengths include the randomized controlled design and a representative high-risk population. Limitations involve the interim analysis nature of the data and underrepresentation of Black patients, which may limit generalizability.

Future Research: Long-term effects on eGFR decline and the potential benefits of combining atrasentan with other therapies, such as SGLT2 inhibitors, warrant further investigation.

Reference: Heerspink HJL, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, Zhang H, et al. Atrasentan in Patients with IgA Nephropathy. New England Journal of Medicine. Published October 25, 2024. DOI: http://doi.org/10.1056/NEJMoa2409415

RCT: ICS-Formoterol and ICS-SABA Reduce Severe Asthma Exacerbations Compared With SABA Alone

28 Oct, 2024 | 18:12h | UTC

Background: Asthma affects millions worldwide and is managed using inhaled relievers to alleviate acute symptoms. While short-acting β agonists (SABA) are commonly used, combining inhaled corticosteroids (ICS) with SABA or formoterol may enhance outcomes. Recent guidelines recommend ICS-formoterol as the preferred reliever, but the optimal choice remains uncertain, especially following the recent FDA approval of ICS-SABA.

Objective: To compare the efficacy and safety of SABA alone, ICS-SABA, and ICS-formoterol as reliever therapies in asthma.

Methods: This systematic review and network meta-analysis included 27 randomized controlled trials involving 50,496 adult and pediatric asthma patients. Trials compared SABA alone, ICS-SABA, and ICS-formoterol as reliever therapies, ensuring similar maintenance treatments across groups. Outcomes assessed were severe asthma exacerbations, asthma symptom control (Asthma Control Questionnaire-5 [ACQ-5]), asthma-related quality of life (Asthma Quality of Life Questionnaire [AQLQ]), adverse events, and mortality.

Results: Compared with SABA alone, both ICS-containing relievers significantly reduced severe exacerbations:

ICS-formoterol: Risk ratio (RR) 0.65 (95% CI, 0.60–0.72); risk difference (RD) –10.3% (95% CI, –11.8% to –8.3%).
ICS-SABA: RR 0.84 (95% CI, 0.73–0.95); RD –4.7% (95% CI, –8.0% to –1.5%).

Compared with ICS-SABA, ICS-formoterol further reduced severe exacerbations (RR 0.78; RD –5.5%). Both ICS-containing relievers modestly improved asthma symptom control compared with SABA alone. No increase in adverse events was observed with either ICS-containing therapy.

Conclusions: Both ICS-formoterol and ICS-SABA as reliever therapies reduce severe asthma exacerbations and improve symptom control compared with SABA alone, without increasing adverse events. ICS-formoterol may offer additional benefits over ICS-SABA in reducing exacerbations.

Implications for Practice: These findings support the use of ICS-containing reliever therapies over SABA alone in asthma management to reduce severe exacerbations and improve control. ICS-formoterol may be preferred when a greater reduction in exacerbations is desired.

Study Strengths and Limitations: High-certainty evidence strengthens these conclusions, but the lack of direct comparisons between ICS-formoterol and ICS-SABA and limited pediatric data are notable limitations.

Future Research: Direct head-to-head trials comparing ICS-formoterol and ICS-SABA, particularly in pediatric populations, are needed to confirm these findings.

Reference: Rayner DG, Ferri DM, Guyatt GH, et al. Inhaled Reliever Therapies for Asthma: A Systematic Review and Meta-Analysis. JAMA. Published online October 28, 2024. DOI: http://doi.org/10.1001/jama.2024.22700

EULAR/PReS Guidelines for the Diagnosis and Management of Still’s Disease

20 Oct, 2024 | 17:41h | UTC

Introduction:

Still’s disease, encompassing systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD), is a systemic inflammatory disorder characterized by spiking fevers, rash, arthralgia or arthritis, and elevated inflammatory markers. Historically treated as separate entities, sJIA and AOSD are now recognized as the same disease continuum. To unify and optimize diagnosis and management across all ages, the European Alliance of Associations for Rheumatology (EULAR) and the Paediatric Rheumatology European Society (PReS) have developed comprehensive, evidence-based recommendations.

Key Recommendations:

Unified Terminology: sJIA and AOSD are the same disease and should be collectively termed “Still’s disease” to standardize diagnosis and treatment. (Recommendation: strong)
Rapid Diagnosis Using Operational Definitions: Key clinical features include spiking fever ≥39°C lasting ≥7 days, transient rash coinciding with fever spikes, arthralgia or arthritis, and elevated inflammatory markers (CRP, ESR, neutrophils, ferritin). Arthritis is supportive but not essential for diagnosis. (Strong)
Diagnostic Biomarkers: Elevated serum interleukin-18 (IL-18) and S100 proteins strongly support the diagnosis and should be measured when available. (Moderate)
Exclude Alternative Diagnoses: Carefully consider infections, malignancies, other immune-mediated inflammatory diseases, and monogenic autoinflammatory disorders to avoid misdiagnosis. (Strong)
Treatment Goals: The ultimate goal is drug-free remission, defined as clinically inactive disease (CID) maintained for at least 6 months. CID entails absence of disease-related symptoms and normalization of ESR and CRP. Intermediate targets at specific time points guide treatment adjustments. (Strong)
Early Use of IL-1 and IL-6 Inhibitors: To avoid prolonged glucocorticoid use, prioritize early initiation of interleukin-1 (IL-1) or interleukin-6 (IL-6) inhibitors upon diagnosis. (Strong)
Glucocorticoid Tapering: Aim to achieve CID without glucocorticoids within 6 months. Maintain CID for 3–6 months before initiating tapering of biologic DMARDs. (Strong)
Monitor for Complications: Be vigilant for life-threatening complications, including macrophage activation syndrome (MAS) and lung disease (LD), which require prompt recognition and management. (Strong)
MAS Management: Consider MAS in patients with persistent fever, splenomegaly, elevated ferritin, cytopenias, abnormal liver function tests, coagulopathy, and hypertriglyceridemia. High-dose glucocorticoids are essential; anakinra, ciclosporin, and interferon-γ inhibitors may be added. (Strong)
LD Screening and Management: Screen patients for LD via clinical assessment and pulmonary function tests; high-resolution CT scans are indicated for symptomatic patients. The presence of LD is not a contraindication for IL-1 or IL-6 inhibitors. (Strong)

Conclusion: Implementing these unified, evidence-based recommendations is expected to improve the diagnosis and management of Still’s disease across all ages, leading to earlier intervention, optimized treatment strategies, reduced complications, and enhanced patient outcomes, including achieving drug-free remission.

Reference: Fautrel B, et al (2024). EULAR/PReS recommendations for the diagnosis and management of Still’s disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still’s disease. Annals of Rheumatic Diseases. DOI: http://doi.org/10.1136/ard-2024-225851

RCT: Milk Elimination Diet Comparable to Four-Food Elimination in Pediatric EoE

20 Oct, 2024 | 15:04h | UTC

Background: Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition characterized by eosinophil infiltration of the esophageal mucosa, leading to symptoms such as nausea, vomiting, abdominal pain, and dysphagia in children. While elimination of six common food allergens is effective, this approach is highly restrictive and may adversely affect quality of life (QoL). Less restrictive diets could potentially balance efficacy with improved QoL.

Objective: To compare the efficacy of a one-food elimination diet excluding milk (1FED) versus a four-food elimination diet excluding milk, egg, wheat, and soy (4FED) in treating pediatric EoE.

Methods: In this multicenter, randomized, nonblinded trial conducted at ten sites in the United States, 63 children aged 6 to 17 years with histologically active and symptomatic EoE were randomized 1:1 to either 1FED (n = 38) or 4FED (n = 25) for 12 weeks. The primary endpoint was symptom improvement measured by the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS). Secondary endpoints included the proportion achieving histologic remission (<15 eosinophils per high-power field), changes in histologic features (histology scoring system), endoscopic severity (endoscopic reference score), transcriptome profiling (EoE diagnostic panel), QoL scores, and predictors of remission.

Results: Out of 63 participants, 51 completed the study (1FED, n = 34; 4FED, n = 17). The 4FED group showed a greater improvement in mean PEESS scores compared to the 1FED group (−25.0 vs. −14.5; P = .04). However, histologic remission rates were similar between 4FED and 1FED (41% vs. 44%; P = 1.00). Changes in the histology scoring system (−0.25 vs. −0.29; P = .77), endoscopic reference score (−1.10 vs. −0.58; P = .47), and QoL scores were comparable between groups. The withdrawal rate was higher in the 4FED group compared to the 1FED group (32% vs. 11%; P = .0496).

Conclusions: While the 4FED moderately improved symptoms more than the 1FED, both diets resulted in similar histologic, endoscopic, QoL, and transcriptomic outcomes. Given its comparable effectiveness, better tolerability, and simplicity, the 1FED is a reasonable first-choice therapy for pediatric EoE.

Implications for Practice: Eliminating cow’s milk alone may be preferable as initial dietary therapy for children with EoE due to its simplicity and similar efficacy compared to more restrictive diets. Clinicians should consider starting with a milk elimination diet before progressing to more restrictive elimination diets if necessary.

Study Strengths and Limitations: Strengths of the study include its randomized, multicenter design; standardized treatment instructions; and use of validated symptom and QoL instruments. Limitations include early termination due to low enrollment, a higher withdrawal rate in the 4FED group, nonblinded interventions, and potential bias from participant expectations.

Future Research: Further large-scale, randomized studies are needed to confirm these findings and to identify biomarkers that predict response to dietary therapy in pediatric EoE.

Reference: Kliewer KL, Abonia JP, Aceves SS, et al. (2024) One-food versus 4-food elimination diet for pediatric eosinophilic esophagitis: A multisite randomized trial. Journal of Allergy and Clinical Immunology. DOI: http://doi.org/10.1016/j.jaci.2024.08.023

Systematic Review: Anifrolumab and Belimumab Improve Disease Control in Systemic Lupus Erythematosus; Voclosporin and Belimumab Effective in Lupus Nephritis

20 Oct, 2024 | 14:26h | UTC

Background: Systemic lupus erythematosus (SLE) management remains challenging due to disease heterogeneity and varying severity. New studies since the 2019 EULAR recommendations necessitate an update to inform clinical practice.

Objective: To analyze new evidence (2018–2022) for SLE management to inform the 2023 update of the European League Against Rheumatism (EULAR) recommendations.

Methods: Systematic literature reviews (SLRs) were conducted in Medline and Cochrane Library databases, covering publications from January 2018 to December 2022. Research focused on five domains: (1) efficacy and safety of SLE treatments, (2) benefits of remission/low disease activity, (3) risks of treatment tapering/withdrawal, (4) management of SLE with antiphospholipid syndrome, and (5) safety of varicella zoster virus (VZV) and SARS-CoV2 immunizations.

Results: A total of 439 relevant articles were identified, predominantly observational studies of low or moderate quality. High-quality randomized controlled trials (RCTs) documented the efficacy of anifrolumab, a type 1 interferon receptor inhibitor, in non-renal SLE, and belimumab and voclosporin, a novel calcineurin inhibitor, in lupus nephritis (LN) when compared with standard care. For specific organ manifestations outside LN, high-quality data were lacking. Multiple observational studies confirmed the benefits of attaining clinical remission or low disease activity, reducing the risk of adverse outcomes. Two RCTs with some concerns found higher relapse rates in patients who discontinued glucocorticoids or immunosuppressants in SLE and LN, respectively; however, observational studies suggest that treatment withdrawal may be feasible in a subset of patients.

Conclusions: Anifrolumab and belimumab achieve better disease control than standard care in extrarenal SLE, while combination therapies with belimumab and voclosporin showed higher response rates in high-quality RCTs in LN. Remission and low disease activity are associated with favorable long-term outcomes. In patients achieving these targets, glucocorticoids and immunosuppressive therapy may be gradually tapered.

Implications for Practice: Clinicians should consider anifrolumab and belimumab for extrarenal SLE, and belimumab and voclosporin for LN. Monitoring and aiming for remission or low disease activity can reduce adverse outcomes. Gradual tapering of glucocorticoids and immunosuppressants may be considered in patients achieving these targets, with careful monitoring for relapse.

Study Strengths and Limitations: Strengths include comprehensive SLRs and inclusion of recent high-quality RCTs. Limitations involve the predominance of low-quality observational studies, lack of high-quality data for specific organ manifestations, and potential bias in treatment withdrawal studies.

Future Research: Further high-quality RCTs are needed to assess treatments for specific organ manifestations outside LN. Long-term studies on tapering and withdrawal strategies of immunosuppressive therapies are necessary to guide safe practice.

Reference: Kostopoulou M, Mukhtyar CB, Bertsias G, Boumpas DT, Fanouriakis A. Management of systemic lupus erythematosus: a systematic literature review informing the 2023 update of the EULAR recommendations. Annals of Rheumatic Diseases. 2023. DOI: https://doi.org/10.1136/ard-2023-225319

RCT: Twice-Yearly Depemokimab Reduced Exacerbations in Severe Eosinophilic Asthma

17 Sep, 2024 | 22:39h | UTC

Background: Severe asthma with an eosinophilic phenotype often leads to frequent exacerbations despite treatment with medium- or high-dose inhaled glucocorticoids and additional controllers. Interleukin-5 is pivotal in eosinophil growth and survival, contributing to airway inflammation. Existing biologic therapies targeting interleukin-5 require frequent dosing intervals. Depemokimab is an ultra-long-acting anti–interleukin-5 biologic with enhanced binding affinity, potentially allowing effective dosing every six months.

Objective: To evaluate the efficacy and safety of twice-yearly depemokimab in reducing exacerbations in patients with severe eosinophilic asthma.

Methods: Two multicenter, randomized, double-blind, placebo-controlled phase 3A trials (SWIFT-1 and SWIFT-2) were conducted. Patients aged ≥12 years with severe asthma and an eosinophilic phenotype (blood eosinophil count ≥300 cells/μL in the previous 12 months or ≥150 cells/μL at screening) and at least two exacerbations in the prior year despite medium- or high-dose inhaled glucocorticoids plus another controller were enrolled. Participants were randomized 2:1 to receive depemokimab 100 mg or placebo subcutaneously at weeks 0 and 26, alongside standard care. The primary endpoint was the annualized rate of exacerbations over 52 weeks. Secondary endpoints included changes from baseline in the St. George’s Respiratory Questionnaire (SGRQ) score, prebronchodilator FEV₁, and asthma symptom scores at 52 weeks.

Results: A total of 792 patients were randomized, with 762 included in the full analysis set (502 depemokimab, 260 placebo). In SWIFT-1, depemokimab significantly reduced the annualized exacerbation rate compared to placebo (0.46 vs 1.11; rate ratio 0.42; 95% CI, 0.30–0.59; P < .001). Similar results were observed in SWIFT-2 (0.56 vs 1.08; rate ratio 0.52; 95% CI, 0.36–0.73; P < .001). No significant between-group differences were found in change from baseline in SGRQ scores. The incidence of adverse events was similar between groups in both trials.

Conclusions: Twice-yearly administration of depemokimab significantly reduced the annualized rate of exacerbations in patients with severe eosinophilic asthma.

Implications for Practice: Depemokimab administered every six months may offer an effective treatment option for reducing exacerbations in severe eosinophilic asthma, potentially enhancing patient adherence and reducing treatment burden associated with more frequent dosing schedules.

Study Strengths and Limitations: Strengths include large, multicenter, randomized, placebo-controlled design and replicate trials confirming efficacy. Limitations involve the lack of significant improvement in quality-of-life measures, low exacerbation rates in the placebo group, potential impact of the COVID-19 pandemic on trial conduct and outcomes, and limited data on certain subpopulations.

Future Research: Further studies are needed to assess long-term safety and efficacy, effects on quality-of-life measures, and the role of depemokimab in broader asthma populations, including those with varying eosinophil counts and biomarker profiles.

Reference: Jackson DJ, et al. (2024) Twice-Yearly Depemokimab in Severe Asthma with an Eosinophilic Phenotype. New England Journal of Medicine. DOI: http://doi.org/10.1056/NEJMoa2406673

Cohort Study: Lower Risk of Cardiovascular Complications in Post–COVID-19 Vaccine Myocarditis Compared to Conventional Etiologies

7 Sep, 2024 | 20:36h | UTC

Study Design and Population: This French nationwide cohort study included 4,635 individuals aged 12-49 hospitalized for myocarditis between December 2020 and June 2022. The cohort was divided into three groups: 558 patients with post–COVID-19 mRNA vaccine myocarditis, 298 with post–COVID-19 infection myocarditis, and 3,779 with conventional myocarditis.

Main Findings: At 18 months of follow-up, the frequency of cardiovascular events was significantly lower in the postvaccine myocarditis group (5.7%) compared to conventional myocarditis (13.2%) with a weighted hazard ratio (wHR) of 0.55 (95% CI, 0.36-0.86). Hospital readmission for myopericarditis occurred in 3.2% of postvaccine cases, 4.0% of post–COVID-19 cases, and 5.8% of conventional cases. The all-cause mortality rate was 0.2% for postvaccine myocarditis, 1.3% for post–COVID-19 myocarditis, and 1.3% for conventional myocarditis.

Implications for Practice: Postvaccine myocarditis patients, primarily young males, experience fewer complications compared to conventional myocarditis, but long-term follow-up is still needed. These findings should guide future mRNA vaccine recommendations and clinical management for myocarditis patients.

Reference: Semenzato L. et al. (2024). Long-term Prognosis of Myocarditis Attributed to COVID-19 mRNA Vaccination, SARS-CoV-2, or Conventional Etiologies. JAMA, Online. DOI: http://doi.org/10.1001/jama.2024.16380

Link: https://jamanetwork.com/journals/jama/fullarticle/2822933

RCT: Zasocitinib Achieves Significant Psoriasis Improvement in Moderate to Severe Plaque Psoriasis

6 Sep, 2024 | 22:48h | UTC

Study Design and Population: This phase 2b, double-blind, placebo-controlled trial evaluated the efficacy, safety, and tolerability of zasocitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, in patients with moderate to severe plaque psoriasis. Conducted across 55 centers in the US and Canada, the study enrolled 287 patients aged 18 to 70 years with a Psoriasis Area and Severity Index (PASI) score ≥12, and ≥10% of body surface area affected. Patients were randomized to receive zasocitinib at doses of 2 mg, 5 mg, 15 mg, or 30 mg, or a placebo, over 12 weeks.

Main Findings: At week 12, significant improvements in PASI were observed across all doses of zasocitinib. The primary endpoint of PASI 75 was achieved in 18%, 44%, 68%, and 67% of patients in the 2 mg, 5 mg, 15 mg, and 30 mg zasocitinib groups, respectively, compared to 6% in the placebo group. Higher PASI 90 and PASI 100 responses were also observed, particularly in the 15 mg and 30 mg groups. Adverse events were mild to moderate and occurred in 53% to 62% of patients receiving zasocitinib, compared to 44% for placebo.

Implications for Practice: Zasocitinib shows promise as an effective and well-tolerated oral treatment for moderate to severe plaque psoriasis. Its efficacy in achieving skin clearance (PASI 75 and above) at higher doses suggests potential for broader clinical use, with phase 3 trials warranted for further validation.

Reference: Armstrong, A.W. et al. (2024). Tyrosine Kinase 2 Inhibition with Zasocitinib in Psoriasis: A Randomized Clinical Trial. JAMA Dermatology. http://doi.org/10.1001/jamadermatol.2024.2701

RCT: Azithromycin Increases Asthma Remission Rates in Adults With Persistent Uncontrolled Asthma

6 Sep, 2024 | 22:35h | UTC

Study Design and Population: This secondary analysis stems from the Asthma and Macrolides: Azithromycin Efficacy and Safety (AMAZES) trial, a randomized, double-anonymized, placebo-controlled trial. The study involved 335 adults with persistent uncontrolled asthma, who were treated with either azithromycin (500 mg, 3 times weekly) or placebo for 12 months. The goal was to evaluate azithromycin’s impact on asthma remission, defined through clinical and lung function measures.

Main Findings: Azithromycin significantly increased the rate of clinical remission compared to placebo (50.6% vs. 38.9%; P = .032). Clinical remission combined with lung function criteria was also higher in the azithromycin group (50.8% vs. 37.1%; P = .029). Although the complete remission rate (including sputum eosinophil count <3%) trended higher, it did not reach statistical significance (23% vs. 13.7%; P = .058).

Implications for Practice: This secondary analysis suggests that azithromycin, when added to standard asthma therapy, could significantly increase remission rates in adults with persistent uncontrolled asthma, including both eosinophilic and noneosinophilic subtypes.

Reference: Thomas, D., M., et al. (2024). Effect of azithromycin on asthma remission in adults with persistent uncontrolled asthma: A secondary analysis of a randomized, double-anonymized, placebo-controlled trial. Chest. https://doi.org/10.1016/j.chest.2024.02.048

News Release – FDA Approves First Nasal Spray for Anaphylaxis Treatment: Neffy (Epinephrine Nasal Spray) – U.S. Food and Drug Administration

17 Aug, 2024 | 15:43h | UTC

The U.S. Food and Drug Administration (FDA) has approved Neffy, the first epinephrine nasal spray for the emergency treatment of anaphylaxis and other severe allergic reactions (Type I) in both adults and pediatric patients weighing at least 30 kilograms (approximately 66 pounds). This approval introduces a non-injectable option for the rapid administration of epinephrine, which is critical in managing life-threatening allergic reactions.

Key Points for Healthcare Providers:

– Alternative to Injection: Neffy provides a new option for patients who may delay or avoid epinephrine injections due to needle phobia. This could be particularly beneficial for children and others reluctant to use injectable epinephrine.

– Efficacy and Safety: Neffy’s approval is supported by studies comparing its pharmacokinetics and pharmacodynamics to traditional epinephrine injections. These studies showed comparable blood epinephrine levels and similar physiological effects, such as increased blood pressure and heart rate.

– Administration: Neffy is a single-dose nasal spray, administered into one nostril. If symptoms do not improve or worsen, a second dose may be administered in the same nostril. Patients should still seek emergency medical care to monitor the anaphylactic reaction.

– Warnings: Certain nasal conditions, such as nasal polyps or a history of nasal surgery, may impair Neffy’s absorption. In these cases, injectable epinephrine might be a more reliable option. The product also carries typical warnings for epinephrine use, particularly in patients with coexisting conditions.

– Side Effects: Common side effects include throat irritation, nasal discomfort, headaches, and jitteriness. Healthcare professionals should discuss these with patients to ensure informed use.

Clinical Implications:

Neffy may reduce barriers to the timely treatment of anaphylaxis, potentially improving outcomes by increasing the likelihood of rapid epinephrine administration. Healthcare providers should consider Neffy as an alternative for patients who are needle-averse or have difficulty using injectable epinephrine, while also ensuring patients understand the importance of prompt medical attention following its use.

Approval Background:

Neffy was granted Fast Track designation by the FDA, emphasizing the need for an alternative to injectable epinephrine. The approval was awarded to ARS Pharmaceuticals.

Source: FDA News Release: FDA Approves First Nasal Spray for Treatment of Anaphylaxis

RCT: Nemolizumab Plus Topical Therapy Improves Skin Clearance, Itch, and Sleep in Moderate-to-Severe Atopic Dermatitis – The Lancet

11 Aug, 2024 | 12:58h | UTC

Study Design and Population: This study reports on two identical 48-week, double-blind, randomized, placebo-controlled phase 3 trials (ARCADIA 1 and ARCADIA 2) involving 1,728 adolescents and adults with moderate-to-severe atopic dermatitis and pruritus unresponsive to topical corticosteroids. Participants were randomized 2:1 to receive nemolizumab (an IL-31 receptor antagonist) or placebo, alongside background topical corticosteroids (TCS) and/or calcineurin inhibitors (TCI).

Main Findings: At week 16, nemolizumab significantly improved primary outcomes compared to placebo, with a higher proportion achieving clear or almost clear skin (IGA success) and a 75% improvement in Eczema Area and Severity Index (EASI-75). Nemolizumab also showed significant early and sustained improvements in itch and sleep. The safety profile was comparable between groups, with treatment-emergent adverse events occurring in about half of the participants.

Implications for Practice: Nemolizumab, in combination with TCS-TCI, demonstrated robust efficacy in reducing inflammation, itch, and sleep disturbances in moderate-to-severe atopic dermatitis. If approved, it could provide an important addition to current treatment options, particularly for patients inadequately managed by existing therapies.

Reference: Silverberg JI, Wollenberg A, Reich A, et al. (2024). Nemolizumab with concomitant topical therapy in adolescents and adults with moderate-to-severe atopic dermatitis (ARCADIA 1 and ARCADIA 2): results from two replicate, double-blind, randomised controlled phase 3 trials. Lancet, 404(10451), 445-460. DOI: 10.1016/S0140-6736(24)01203-0.

Nested Case-Control Study: Sulfonamide Antibiotics and Cephalosporins Linked to Highest Risk of Serious Cutaneous Adverse Drug Reactions – JAMA

10 Aug, 2024 | 21:16h | UTC

Study Design and Population: This population-based, nested case-control study assessed the risk of serious cutaneous adverse drug reactions (cADRs) among older adults (66 years and above) in Ontario, Canada, who received oral antibiotics between 2002 and 2022. The study included 21,758 cases of emergency department visits or hospitalizations for serious cADRs, matched with 87,025 controls.

Main Findings: The study found that sulfonamide antibiotics (adjusted odds ratio [aOR], 2.9) and cephalosporins (aOR, 2.6) posed the highest risk of serious cADRs compared to macrolides. Nitrofurantoin, penicillins, and fluoroquinolones also showed elevated risks. Cephalosporins had the highest crude rate of cADRs (4.92 per 1,000 prescriptions).

Implications for Practice: The findings suggest that clinicians should consider the higher risks of serious cADRs associated with sulfonamide antibiotics and cephalosporins when prescribing antibiotics, opting for lower-risk alternatives when appropriate.

Reference: Lee EY et al. (2024). Oral Antibiotics and Risk of Serious Cutaneous Adverse Drug Reactions. JAMA. Published online August 8, 2024. DOI: 10.1001/jama.2024.11437.

Diagnostic Study: Enhanced prediction of TB progression with IGRAs compared to tuberculin skin test

27 Apr, 2024 | 18:53h | UTC

Study Design and Population:

This prospective diagnostic study analyzed the predictive accuracy of tuberculosis (TB) tests among 22,020 high-risk participants across 10 US sites from 2012 to 2020. Participants included individuals with close contacts to infectious TB cases, those born in or travelers to high-incidence countries, individuals living with HIV, or belonging to locally prevalent high-risk groups. Testing included two interferon-γ release assays (IGRAs), QuantiFERON-TB Gold In-Tube (QFT-GIT) and SPOT.TB (TSPOT), alongside the traditional tuberculin skin test (TST).

Main Findings:

The study found that both IGRAs, TSPOT and QFT-GIT, showed significantly superior positive predictive value (PPV) for predicting TB disease progression compared to the TST, with PPV ratios of 1.65 (95% CI, 1.35-2.02) and 1.47 (95% CI, 1.22-1.77) respectively. Additionally, when considering a positive TST result, further positive results from either IGRA significantly increased the PPV, emphasizing the enhanced predictive capability of IGRAs over TST alone.

Implications for Practice:

The superior predictive performance of Interferon-γ Release Assays (IGRAs) suggests they should be considered in clinical settings for high-risk populations, if available and feasible, to better identify individuals at increased risk of progressing to active tuberculosis (TB). This enhanced detection capability could guide more targeted preventive treatments, ultimately supporting global efforts toward TB elimination. Clinicians should assess the accessibility and cost-effectiveness of IGRAs to refine decision-making processes in TB prevention strategies, ensuring that the benefits of these advanced diagnostics are balanced against their costs.

Reference (free full-text):

Ayers, T. et al. (2024). Comparison of Tuberculin Skin Testing and Interferon-γ Release Assays in Predicting Tuberculosis Disease. JAMA Network Open, 7(4), e244769. DOI: https://doi.org/10.1001/jamanetworkopen.2024.4769.

Study | Removal of thymus in adults linked to increased death, cancer incidence

4 Aug, 2023 | 12:09h | UTC

Health Consequences of Thymus Removal in Adults – New England Journal of Medicine (link to abstract – $ for full-text)

Commentaries:

Doctors have long considered the thymus expendable. But could removing it be fatal? – Science

The thymus withers away after puberty. But it may be important for adults – Science News

Thymus gland critical for adult health, study finds – News Medical

Commentary on Twitter

In a study by Kooshesh et al., mortality, the risk of cancer, and levels of proinflammatory cytokines were higher among adults whose thymus had been removed than among control patients. Read the full study results: https://t.co/poaAiELsKG

— NEJM (@NEJM) August 2, 2023